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Recessive or co-dominant single-gene mutations disrupting leptin melanocortin pathway cause severe obesity and hyperphagia. Since Pakistan has a very high rate of consanguinity, therefore, a significantly higher incidence of monogenic obesity is expected in its population. We have assessed the incidence of LEP and MC4R mutations and associated hormonal profiles, in a cohort of randomly selected Pakistani children with early onset of severe obesity. Sixty two unrelated children of consanguineous parents, with a weight-for-age percentile >97 were recruited in the study. Screening for mutations in the coding regions of LEP and MC4R was performed by direct sequencing. Serum hormone concentrations were determined by immunoassay. LEP mutations were found in 16.1% of the probands. Of these, 9 probands carried the homozygous frameshift mutation, G133_VfsX14, whereas one patient had a homozygous mutation involving deletion of 3 base pairs, (I35del). In these probands, leptin levels were very low or undetectable and insulin levels were increased in 33%. Homozygous MC4R mutations, M161T and I316S, identified separately in 2 subjects (3.2%), were associated with severe obesity, hyperphagia, hyperleptinemia and hyperinsulinemia. The heterozygous M161T sibling had normal body weight and hormone levels and the parents were only mildly overweight. Based on genetic analysis of LEP and MC4R genes only, we elucidated genetic causality of severe obesity in 20% of our patients confirming high prevalence of monogenic form of obesity in this consanguineous population. Co-dominancy of MC4R is exacerbated in this group with non-penetrance of obesity in heterozygous loss-of-function MC4R mutation carriers. The sub-ethnic specificity of LEP mutation, G133_VfsX14, suggests a founder effect., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Obesity in children can lead to morbidity and mortality due to metabolic and inflammatory comorbidities. Aims: The objective of the study was to investigate the alterations in acute inflammatory markers, serum amyloid P (SAP) and cortisol, and endocrine markers, leptin and insulin, in obese children. Materials and Methods: Serum leptin, insulin, cortisol, and amyloid P concentrations were measured in obese (BMI percentile >85, n = 17) and nonobese (BMI percentile < 75, n = 20) children using ELISA and Bio-Plex Bead-based assay. Statistical Analysis Used: Serum concentrations of analytes were compared between normal and obese groups using 2-tailed student's t-test. Results: Mean leptin, insulin, and SAP serum concentrations were significantly higher in obese children as compared to the controls (97.19 vs. 4.06, P < 0.05; 21.31 vs 3.56, P < 0.05; 46.77 vs. 17.89, P < 0.05; respectively). No difference was found in mean serum cortisol levels of the two groups. However, cortisol values were higher in obese subjects compared to the control group (7.89 vs 6.30, P = 0.15). Leptin corelated with insulin (r = 0.42, P = 0.043) and cortisol (r = 0.48, P = 0.025) levels in the obese group. Furthermore, leptin, insulin, and SAP levels were corelated with BMI (r = 0.80, P < 0.000; r = 0.67, P = 0.015, respectively) and body weight (r = 0.52, P = 0.01; r = 0.52, P = 0.002; r = 0.54, P = 0.01, respectively) in the obese group but did not demonstrate a significant relationship in the nonobese group. Conclusion: Elevated SAP levels and increase in leptin and insulin indicated a preeminent disposition of morbidly obese children to the development of low-grade inflammation and metabolic syndrome. [ABSTRACT FROM AUTHOR]